tbuckley/cabot-search huggingface dataset:
Abstract 1459: Identification of transcription factor enrichments in HPV+ head and neck cancer using ChIP-seq and cistrome analysis
Authors: Fernando Zamuner, Spencer S. Chan, Michael Kessler, Ilya Vorontsov, Ludmila Danilova, Rossin Erbe, Dylan Kelley, Theresa Guo, Eddie Imada, Elana J. Fertig, Ivan Kulakovskiy, Alexander Favorov, Daria A. Gaykalova
Journal: Cancer Research (2022)

Abstract The subset of head and neck squamous cell carcinomas (HNSCC) that are driven by infection with the Human Papilloma Virus (HPV+ HNSCC) are increasing in prevalence and are defined by distinct biological signatures and mechanisms, such as abnormal transcriptional regulation. Here, we use optimized protocols to perform ChIP-seq and RNA-seq on patient surgical samples, which we use to define promoter, typical-enhancer, and super-enhancer (SE) regulatory regions with differential chromatin states (i.e. H3K27ac signal) between tumor and normal samples. We then leverage publicly available transcription factor (TF) cistrome data to test 372 TFs for tumor or normal specific enrichment across these differential regulatory regions. We identify 31 tumor-specific TF enrichments, such as TP53/63/73, NKX2-1, JUNB/D, FOSL1/2, E2F1/3, KLF3/4/5, SMAD3/4, TEAD1/4, TFAP2A/C, HIF1A, PPARG, GRHL2, EPAS1, and SNAI2. A number of these enriched TFs, including TP63, TP73, FOSL1, and E2F1, show both significantly increased expression in tumors and significant transcriptional reductions after JQ1 treatment. These results provide novel insight into the regulatory biology of HPV+ HNSCC, and suggest that the transcriptional networks and feedback loops governing TF expression and dysregulation in HPV+ HNSCC can be targeted using JQ1 treatment. Citation Format: Fernando Zamuner, Spencer S. Chan, Michael Kessler, Ilya Vorontsov, Ludmila Danilova, Rossin Erbe, Dylan Kelley, Theresa Guo, Eddie Imada, Elana J. Fertig, Ivan Kulakovskiy, Alexander Favorov, Daria A. Gaykalova. Identification of transcription factor enrichments in HPV+ head and neck cancer using ChIP-seq and cistrome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1459.
Abstract 6317: Molecular subtyping in prostate cancer associate with outcomes to abiraterone and ipatasertib treatment from the phase III IPATential150 trial
Authors: Zhen Shi, Malgorzata Nowicka, Johann de Bono, Kim N. Chi, Christopher Sweeney, Cora N. Sternberg, David Olmos, Sergio Bracarda, Christophe Massard, Nobuaki Matsubara, Josep Garcia, Geng Chen, Matthew Wongchenko, Shahneen K. Sandhu
Journal: Cancer Research (2022)

Abstract Prostate cancer is a heterogeneous disease and genomic subtyping offers an opportunity to better understand underlying disease biology. Here, we performed transcriptional profiling by RNA-Seq (n=582) and targeted genomic sequencing by FoundationONE CDx (n=743) from prostate cancer tumor specimens in the phase III IPATential150 trial of first-line ipatasertib (Ipat) plus abiraterone (Abi) in metastatic castration-resistant prostate cancer (N=1101). Unsupervised transcriptomic analysis of the 582 samples with RNA-Seq with Nonnegative Matrix Factorization (NMF) reveals four consensus subtypes. This includes an immune/cell cycle-high, an AR signature/cell cycle-high, a stroma program-enriched, and an ERG fusion-enriched subtype. Subgroups of patients with immune/cell cycle-high and AR signature/cell cycle-high tumors had the shortest radiographic progression-free survival (rPFS) and were characterized by high MYC and cell cycle-related gene signatures. Patients with AR signature/cell cycle-high tumors showed the greatest increase in rPFS with Ipat + Abi vs. Placebo (Pbo) + Abi (HR = 0.58). Cluster n Enriched processes Median rPFS (Pbo + Abi) (months, 95% CI) Median rPFS (Ipat + Abi) (months, 95% CI) HR (95% CI) NMF1 84 Immune processes, metabolism, cell cycle 10.3 (8.3 - 12.7) 13.9 (10.9 - 16.4) 0.77 (0.47 - 1.28) NMF2 165 Androgen response signature, cell cycle, MYC signature 11.9 (8.8 - 16.5) 20.9 (16.4 - NA) 0.58 (0.38 - 0.90) NMF3 156 Fibroblast, Wnt, Notch, Hedgehog, TGFb 20.0 (16.4 - NA) 22.3 (15.6 - 24.9) 0.96 (0.59 - 1.56) NMF4 177 ERG fusion 18.4 (13.8 - 23.8) 24.7 (16.2 - NA) 0.78 (0.50 - 1.20) Citation Format: Zhen Shi, Malgorzata Nowicka, Johann de Bono, Kim N. Chi, Christopher Sweeney, Cora N. Sternberg, David Olmos, Sergio Bracarda, Christophe Massard, Nobuaki Matsubara, Josep Garcia, Geng Chen, Matthew Wongchenko, Shahneen K. Sandhu. Molecular subtyping in prostate cancer associate with outcomes to abiraterone and ipatasertib treatment from the phase III IPATential150 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6317.
Abstract 6325: Identification of genes responsible for osteosarcomas metastatic evolution by active super enhancers profiling
Authors: Mélanie Lavaud, Robel Tesfaye, Céline Charrier, Rose Anne Thépault, Maxime Golias, Sarah Le Page, Mathilde Mullard, Bénédicte Brounais, Franck Verrecchia, Marc Baud'huin, François Lamoureux, Steven Georges, Benjamin Ory
Journal: Cancer Research (2022)

Abstract Super enhancers are strong spatiotemporal transcriptional regulators. They can be mapped on genomes thanks to their astounding enrichment for well-known enhancers markers, such as acetylation of the lysine 27 of type 3 histones (H3K27Ac). Their target genes, confined in their so-called topologically associated domains, present exceptionally high expression levels, depending on associated super enhancers activation status, and are responsible for defining cells identity whether physiological or pathological. Osteosarcomas are the most common primary malignant bone tumors. Patients suffering from osteosarcomas, on average 15 years old, mostly develop pulmonary metastasis, responsible for drastic decrease in their survival. We have conducted chromatin immunoprecipitation sequencing against H3K27Ac and RNA sequencing experiments on osteosarcoma cells presenting high propensity to metastatic dissemination or devoid of this capacity, in order to unveil genes implicated in metastasis development through super enhancers genomic mapping. We have highlighted exclusive active super enhancers profiles between metastatic and non-metastatic osteosarcoma cells. Among target genes of spotted super enhancers, three of them caught our attention. Implication of these genes in metastatic development have already been demonstrated in various cancers evolution, except in osteosarcomas. Osteosarcoma cells having high capacity for metastatic development present identified genes over expressions compared to cells incompetent in this pathological process. Artificial down expressions of identified genes decrease osteosarcoma cells metastatic capacity in vitro. In vivo experiments, that correspond to paratibial implantation of modified osteosarcoma cells and analysis of primary tumor metastatic development, are currently under way. Our strategy may allow identification of new therapeutic targets to fight against osteosarcoma metastatic evolution and open new perspectives to improve patients prognostic. This work is funded by Ligue contre le cancer, ANR, SFCE and Région Pays de la Loire. Citation Format: Mélanie Lavaud, Robel Tesfaye, Céline Charrier, Rose Anne Thépault, Maxime Golias, Sarah Le Page, Mathilde Mullard, Bénédicte Brounais, Franck Verrecchia, Marc Baud'huin, François Lamoureux, Steven Georges, Benjamin Ory. Identification of genes responsible for osteosarcomas metastatic evolution by active super enhancers profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6325.
Abstract 1875: Novel cell-based bioassays for monoclonal antibody and bispecific molecules in PD-1 blockade monotherapy and combination therapy
Authors: Jamison Grailer, Julia Gilden, Jun Wang, Denise Garvin, Pete Stecha, Jim Hartnett, Steven Edenson, Frank Fan, Mei Cong, Zhi-jie Jey Cheng
Journal: Cancer Research (2022)

Abstract Programmed death 1 (PD-1) is an immune checkpoint (IC) receptor that negatively regulates T-cell immune function. Blocking the interaction of PD-1 with its ligand PD-L1 unleashes the immune system and enhances anti-tumor responses. Immunotherapy using PD-1 blockade has led to a paradigm shift in cancer drug discovery, due to its durable effect against a wide variety of cancers. However, despite its tremendous clinical success in cancer treatment, a significant fraction of patients and tumor types remain unresponsive to this therapy. This has led to the development of combination therapies combining PD-1 checkpoint inhibitors with a broad range of clinically active treatments including those targeting other IC receptors. A major challenge in immunotherapy drug development is the lack of quantitative and reproducible functional assays as existing methods rely heavily on primary immune cells and are highly variable. Here, we report the development of a suite of cell line-based reporter bioassays for monoclonal antibody targeting human PD-1/PD-L1, or bispecific molecules target PD-1/PD-L1 and a co-stimulatory receptor (e.g., 4-1BB, OX40, ICOS) or an immune inhibitory receptor (e.g., CTLA-4, LAG-3, TIGIT). A mouse PD-1/PD-L1 assay and a human PD-1/PD-L2 assay are also developed and can be used in parallel with human PD-1/PD-L1 assay to address preclinical study and assay specificity. Each of these assays consist of two engineered cell lines: a T effector cell line that express a luciferase reporter driven by specific promoter/response elements responding to the intracellular signals mediated by the T cell receptor (TCR), PD-1 and the second IC receptor, and an artificial antigen presenting cells (aAPCs). Particularly, the combination bioassays are able to measure the synergetic effect of PD-1 blockade with a second IC inhibitor receptor blockade or a costimulatory receptor activation. These reporter-based assays reflect the mechanisms of action for the therapeutic drugs of interest and are sensitive and quantitative. They are prequalified according to ICH guideline and demonstrated the performance characteristics (specificity, precision, accuracy, and linearity) to be used as potency assay for product release and stability studies during immunotherapy drug development and manufacture. Citation Format: Jamison Grailer, Julia Gilden, Jun Wang, Denise Garvin, Pete Stecha, Jim Hartnett, Steven Edenson, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Novel cell-based bioassays for monoclonal antibody and bispecific molecules in PD-1 blockade monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1875.
Abstract 6322: Dynamic, stage-course protein interaction network using high power CpG sites in head and neck squamous cell carcinoma
Authors: Arsalan Riaz, Faisal Khan
Journal: Cancer Research (2022)

Abstract Head and neck cancer is the most incident and prevalent cancer in men in South Asian countries, especially Pakistan. Prediction of pathological stages of cancer can play a critical role in early diagnosis and personalized medicine. This project ventures into the prediction of different stages of head and neck squamous cell carcinoma (HNSCC) using prioritized DNA methylation patterns. DNA methylation profiles for each HNSCC stage (stage-I-IV) were used to extensively analyze 485,577 methylation CpG sites and prioritize them on the basis of the highest predictive power using a wrapper-based feature selection method, along with different classification models. We identified 68 high-power methylation sites which predicted the pathological stage of HNSCC samples with 90.62% accuracy using a Random Forest classifier. We set out to construct a protein-protein interaction network for the proteins encoded by the 67 genes associated with these sites to study its network topology and also undertook enrichment analysis of nodes in their immediate neighborhood for GO and KEGG Pathway annotations revealing their role in cancer-related pathways, cell differentiation, signal transduction, metabolic and biosynthetic processes. With information on the predictive power of each of the 67 genes in each HNSCC stage, we unveil a dynamic stage-course network for HNSCC that evolves over the course of the four cancer stages. We intend to further study these genes in light of functional datasets from CRISPR, RNAi, drug screens for their putative role in HNSCC initiation and/or progression. Citation Format: Arsalan Riaz, Faisal Khan. Dynamic, stage-course protein interaction network using high power CpG sites in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6322.
Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC
Authors: Muyiwa Awoniyi, Jeremy Wang, Billy Ngo, Vik Meadows, Jason Tam, Amba Viswanathan, Yunjia Lai, Stephanie Montgomery, Morgan Farmer, Martin Kummen, Louise Thingholm, Christoph Schramm, Corinna Bang, Andre Franke, Kun Lu, Huiping Zhou, Jasmohan S Bajaj, Phillip B Hylemon, Jenny Ting, Yury V Popov, Johannes Roksund Hov, Heather L Francis, Ryan Balfour Sartor
Journal: Gut (2022)

Objective Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient ( mdr2 −/− ) mice and microbial profiles in PSC patient cohorts. Design We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2 −/− mice and targeted metagenomic analysis in PSC patients. Results GF mdr2 −/− mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2 −/− mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2 −/− mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients’ clinical severity by Mayo risk scores. Conclusions We identified novel functionally protective and detrimental resident bacterial species in mdr2 −/− mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.
Association of Tumor Mutational Burden with Efficacy of Pembrolizumab±Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
Authors: Keun-Wook Lee, Eric Van Cutsem, Yung-Jue Bang, Charles S. Fuchs, Iveta Kudaba, Marcelo Garrido, Hyun Cheol Chung, Jeeyun Lee, Hugo R. Castro, Joseph Chao, Zev A. Wainberg, Z. Alexander Cao, Deepti Aurora-Garg, Julie Kobie, Razvan Cristescu, Pooja Bhagia, Sukrut Shah, Josep Tabernero, Kohei Shitara, Lucjan Wyrwicz
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab±chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P &amp;lt; 0.05) but not with chemotherapy (all P &amp;gt; 0.05). The overall prevalence of TMB ≥10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB ≥10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+chemotherapy) with TMB ≥10 mut/Mb. When the analysis was limited to the non–MSI-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first-line pembrolizumab-based therapy in patients with advanced gastric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.
Abstract 867: Velcrin-induced cleavage of tRNA-Leu-TAA by SLFN12 RNase causes cancer cell death
Authors: Sooncheol Lee, Stephanie Hoyt, Xiaoyun Wu, Colin Garvie, Joseph McGaunn, Andrew D. Cherniack, Matthew Meyerson, Heidi Greulich
Journal: Cancer Research (2022)

Abstract Velcrins are small molecules that induce apoptosis of cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) by inducing PDE3A-SLFN12 complex formation. Recently, we found that SLFN12 is an RNase and PDE3A binding dramatically activates SLFN12 RNase activity, resulting in velcrin-mediated apoptosis. However, the mechanism of cancer cell death by the PDE3A-SLFN12 complex is poorly understood. In this study, we found that SLFN12 specifically recognizes tRNA-Leu-TAA and induces its cleavage in velcrin-sensitive cell lines. According to tRNA-sequencing, tRNA-Leu-TAA isodecoders decreases by 2-fold to 5-fold in Hela cells treated with DNMDP compared to DMSO control, while other tRNAs are not differentially expressed. Down-regulation of tRNA-Leu-TAA by velcrin treatment is observed only in velcrin-sensitive cell lines but not insensitive cell lines. Furthermore, we tested whether SLFN12 digests tRNA-Leu-TAA in vitro. Purified wild-type SLFN12 cleaves tRNA-Leu-TAA but not heat-denatured or catalytically inactive SLFN12. Even though tRNA-Leu-TAA is weakly digested by low concentrations of SLFN12, co-incubation with purified PDE3A increases SLFN12 RNase activity, which is even further upregulated by velcrin treatment. To verify specificity for tRNA-Leu-TAA, we assessed activity of SLFN12 against a panel of in vitro transcribed tRNAs. We found that purified SLFN12 is significantly more efficient at degrading tRNA-Leu-TAA when compared with tRNA-Leu-TAG or tRNAs for other amino acids. Digestion of tRNA-leu-TAA by SLFN12 could inhibit mRNA translation due to the delivery of leucine amino acid to elongating ribosomes. To test this hypothesis, we designed the mutant tRNA-Leu-[CAG:TAA] in which the anticodon of tRNA-Leu-CAG was replaced by TAA anticodon. Ectopic expression of wild-type tRNA-Leu-TAA or tRNA-Leu-CAG has no effect on viability of DNMDP-treated cells, whereas expression of tRNA-Leu-[CAG:TAA] genes partially rescues the cells from DNMDP-induced cytotoxicity. These data confirm that impaired leucine delivery is responsible at least in part for the observed effects of DNMDP treatment. Citation Format: Sooncheol Lee, Stephanie Hoyt, Xiaoyun Wu, Colin Garvie, Joseph McGaunn, Andrew D. Cherniack, Matthew Meyerson, Heidi Greulich. Velcrin-induced cleavage of tRNA-Leu-TAA by SLFN12 RNase causes cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 867.
Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer
Authors: Guillaume Fonteneau, Alexandra Redding, Hannah Hoag-Lee, Edward S. Sim, Stefan Heinrich, Matthias M. Gaida, Elda Grabocka
Journal: Cancer Discovery (2022)

Obesity is a global epidemic and a major predisposing factor for cancer. Increasing evidence shows that obesity-associated stress is a key driver of cancer risk and progression. Previous work has identified the phase-separation organelles, stress granules (SG), as mutant KRAS-dependent mediators of stress adaptation. However, the dependence of tumorigenesis on these organelles is unknown. Here, we establish a causal link between SGs and pancreatic ductal adenocarcinoma (PDAC). Importantly, we uncover that dependence on SGs is drastically heightened in obesity-associated PDAC. Furthermore, we identify a previously unknown regulator and component of SGs, namely, the serine/arginine protein kinase 2 (SRPK2), as a specific determinant of SG formation in obesity-associated PDAC. We show that SRPK2-mediated SG formation in obesity-associated PDAC is driven by hyperactivation of the IGF1/PI3K/mTOR/S6K1 pathway and that S6K1 inhibition selectively attenuates SGs and impairs obesity-associated PDAC development.: We show that stress adaptation via the phase-separation organelles SGs mediates PDAC development. Moreover, preexisting stress conditions such as obesity are a driving force behind tumor SG dependence, and enhanced SG levels are key determinants and a chemopreventive target for obesity-associated PDAC. This article is highlighted in the In This Issue feature, p. 1825.